Euphorbiasteroid induces neurotoxicity through the FOXO/NF-κB/apoptosis signaling pathway

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2024-11-13 DOI:10.1016/j.brainresbull.2024.111129

Jianwen Chen , Yuheng Wang , Zhengxu Cai

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引用次数: 0

Abstract

Background

Euphorbiasteroid, a bioactive compound from Euphorbia lathyris L., exhibits significant pharmacological effects, including anti-tumor activity and multi-drug resistance reversal. However, its potential neurotoxicity limits its clinical use. This study investigates the neurotoxic effects of euphorbiasteroid and elucidates the underlying mechanisms.

Methods

Neurotoxicity was evaluated in differentiated PC12 cells and primary astrocytes through cell viability and lactate dehydrogenase (LDH) assays. Transcriptomic analysis was employed to predict the involvement of the Forkhead box O (FOXO), nuclear factor-kappa B (NF-κB), and apoptosis pathways in euphorbiasteroid-induced cytotoxicity. Apoptosis was detected using TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and western blot analysis of quantified apoptotic markers and key signaling proteins. Molecular docking studies explored the interaction between euphorbiasteroid and FOXO3A, while gene knockdown experiments assessed the role of FOXO3A.

Results

Euphorbiasteroid significantly induced cytotoxicity in differentiated PC12 cells and primary astrocytes, linked to the activation of the FOXO, NF-κB, and apoptosis pathways. Apoptosis was confirmed by TUNEL staining, Bax/Bcl-2 ratio, and cleaved caspase 3 levels. Additionally, euphorbiasteroid reduced phospho-FOXO3A levels, promoted FOXO3A nuclear translocation and enhanced NF-κBp65 phosphorylation. Molecular docking revealed direct binding of euphorbiasteroid to FOXO3A, and FOXO3A knockdown substantially mitigated its neurotoxicity.

Conclusion

Euphorbiasteroid induces neurotoxicity through the activation of the FOXO/NF-κB/apoptosis signaling pathway. These findings provide new insights into the mechanisms of euphorbiasteroid-induced neurotoxicity and suggest potential strategies to mitigate these effects, which is crucial for its therapeutic application.

查看原文本刊更多论文

大戟提取物通过FOXO/NF-κB/细胞凋亡信号通路诱导神经毒性。

背景：大戟生物碱（Euphorbiasteroid）是从大戟科植物矢车菊（Euphorbia lathyris L.）中提取的一种生物活性化合物，具有显著的药理作用，包括抗肿瘤活性和逆转多重耐药性。然而，其潜在的神经毒性限制了其临床应用。本研究调查了玉竹的神经毒性作用，并阐明了其潜在机制：方法：通过细胞存活率和乳酸脱氢酶（LDH）测定评估了分化 PC12 细胞和原发性星形胶质细胞的神经毒性。通过转录组分析，预测叉头盒O（FOXO）、核因子-卡巴B（NF-κB）和细胞凋亡通路在极紫草素诱导的细胞毒性中的参与情况。采用 TdT 介导的 dUTP 镍末端标记（TUNEL）染色法检测细胞凋亡，并对量化的细胞凋亡标记物和关键信号蛋白进行免疫印迹分析。分子对接研究探讨了玉竹和FOXO3A之间的相互作用，而基因敲除实验则评估了FOXO3A的作用：结果：Euphorbiasteroid能明显诱导分化的PC12细胞和原代星形胶质细胞产生细胞毒性，这与FOXO、NF-κB和细胞凋亡通路的激活有关。细胞凋亡通过 TUNEL 染色、Bax/Bcl-2 比率和裂解的 caspase 3 水平来证实。此外， euphorbiasteroid 还降低了磷酸-FOXO3A 的水平，促进了 FOXO3A 的核转位，并增强了 NF-κBp65 的磷酸化。分子对接显示 euphorbiasteroid 与 FOXO3A 直接结合，而 FOXO3A 的敲除大大减轻了其神经毒性：结论：Euphorbiasteroid通过激活FOXO/NF-κB/细胞凋亡信号通路诱导神经毒性。这些发现为了解大戟酰基雄甾醇诱导神经毒性的机制提供了新的视角，并提出了减轻这些效应的潜在策略，这对大戟酰基雄甾醇的治疗应用至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.